OVERVIEW: What every practitioner needs to know

Are you sure your patient has Mycoplasma pneumoniae infection? What are the typical findings for this disease?

Mycoplasma pneumoniae is a common cause of upper respiratory tract infection, and remains the most common cause of bacterial pneumonia. The term, "walking pneumonia," has been used to describe the usual case of lower respiratory tract infection, as the illness is not usually debilitating. Extrapulmonary manifestations and complications of mycoplasma infection are encountered on a regular basis, and include rash, arthritis, hemolytic anemia, central nervous system disorders, pericarditis, renal dysfunction, and gastrointestinal complaints.

The typical respiratory infection caused by M. pneumoniae is a slowly evolving syndrome of pharyngitis, sinus congestion, and dry cough. During this phase, the cough is secondary to tracheobronchitis. When the infection progresses to involve the lower respiratory tract, atypical pneumonia with bilateral diffuse pulmonary infiltrates is most common.

Extrapulmonary manifestations of infection

Approximately 20% of patients who are hospitalized with M. pneumoniae infection develop an extrapulmonary complication. Dermatologic disorders, including an erythematous maculopapular rash are among the most common extrapulmonary manifestations of illness. Rashes are usually self-limited; however, severe forms of erythema multiforme major, conjunctivitis, ulcerative stomatitis, and bullous exanthems do occur.

Erythema multiforme major and Mycoplasma infection

Erythema multiforme major, or Steven Johnson syndrome, can be triggered by several known infecting agents. One of the most common known triggers for this multisystem inflammatory disorder is M. pneumoniae. Patients who develop this problem should be evaluated for the possibility of mycoplasma infection.

What caused this disease to develop at this time?

Mycoplasma pneumoniae infections can occur as clusters and outbreaks in all age groups. Climate, seasonality, and geography do not appear to contribute to the spread of the agent, although most outbreaks described in the United States occur in the late summer and early fall.

Children with sickle cell disease, Down syndrome, and immunosuppression are at higher risk for severe mycoplasma disease, including fulminant pneumonia. Children with antibody deficiency syndromes are at greater risk for pulmonary disease and have a predisposition to the development of arthritis caused by M. pneumoniae.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Serologic diagnosis has been considered the gold standard for disease confirmation when a four-fold rise in serum antibody is detected between acute and convalescent samples. Mycoplasma culture and PCR are also used, but because the organism can persist for variable lengths of time, the significance of a positive culture or PCR result may be called into question without supporting evidence of seroconversion.

Serologic testing

Acute and convalescent titers should be obtained approximately 4-6 weeks apart. A four-fold or higher rise in anti-mycoplasma antibody titer supports the clinical diagnosis. Serologic diagnosis remains the 'gold standard' used to confirm the microbiologic etiology of the illness, although other test results, such as cold agglutinin titers and mycoplasma PCR, can provide supporting evidence during the acute phase of infection.

Cold Agglutinin Titers

Cold agglutinins are IgM antibodies that are produced in roughly half of patients with Mycoplasma pneumoniae infection 7-10 days into the illness. These antibodies are thought to be cross-reactive antibodies developed against the I antigen of erythrocytes. So-called 'bed-side' cold agglutinin testing involves collecting blood into an anticoagulated tube and placing the tube into ice water for 30 seconds. The tube is then inspected for macroagglutination while cold, then slowly warmed to observe separation of the erythrocytes. On re-exposure to cold, the macroagglutination recurs.

A more precise test involves diluting sera serially, and reacting the sera with blood group O blood type erythrocytes to determine the titer to which the agglutination still occurs. This test is routinely performed in blood bank laboratories. The cold agglutinin response has been shown to correlate directly with the severity of respiratory illness; however, the test is insensitive and highly non-specific. With more routine availability of serologic and PCR diagnosis, the popularity and utility of this test has dwindled. A positive bed-side cold agglutinin test performed on blood obtained from a patient with atypical pneumonia or erythema multiforme, however, can be clinically satisfying, as it offers convincing supportive evidence for the cause of the patient's illness.

Mycoplasma culture

Laboratory culture of Mycoplasma pneumoniae is technically challenging and only available in specialized reference laboratories. Selective and differential culture medium is required to support its growth, the organism grows very slowly (3 weeks or more), and the bacterial colonies need to be visualized microscopically by an experienced microbiologist to confirm growth and identify the mycoplasma species as pneumoniae. Culture is, therefore, impractical, and of little clinical use, because the patient will likely be recovered from the illness before the culture result is known.

Mycoplasma PCR

Polymerase chain reaction is a rapid, highly sensitive, and specific assay used to detect the presence of microbe-specific nucleotide. Culture is insensitive and slow, and serology requires acute and convalescent samples obtained at least a month apart, so it is understandable that PCR assays have been developed to assist in diagnosing Mycoplasma infections.

Limitations to PCR testing need to be recognized. First, PCR positive samples can be detected in clinically asymptomatic individuals. Mycoplasma organisms and/or mycoplasma-specific DNA may be present for weeks or months following infection, so the detection of PCR amplicons from a patient may not reflect active infection. To overcome this limitation, a combined use of mycoplasma IgM testing with PCR testing has been proposed for use in children. Clinical samples that are suitable for PCR testing include respiratory secretions obtained from the oropharynx, nasopharynx, sputum, or bronchoalveolar lavage fluid. Direct PCR from lung tissue has also been successful.

Role for IgA Testing

Since M. pneumoniae is a mucosal infection, the possibility of using organism-specific IgA responses to establish a diagnosis has been suggested. Very few assays currently include reagents for IgA testing, and, at the present time, IgA-specific assays are unavailable in the United States.

Would imaging studies be helpful? If so, which ones?

A chest radiograph should be obtained in patients with moderate to severe respiratory symptoms to document the extent of pulmonary involvement, identify the presence of any pleural effusions, and to evaluate for the rare complication of lung abscess.

Radiographic findings in Mycoplasma pneumoniae infection are extremely variable and can, therefore, mimic a variety of other conditions. The most likely radiographic findings are those of bronchopneumonia of the perihilar regions. Lobar pneumonia and the presence of pleural effusions are seen less frequently. Radiographic evidence of lung abscess has been described during mycoplasma infection, but their presence should always raise the possibility of an alternate diagnosis.

If you are able to confirm that the patient has a Mycoplasma pneumoniae infection, what treatment should be initiated?

Appropriate antibiotic treatment of mycoplasma infection shortens the course of the illness and speeds alleviation of symptoms. Macrolide group antibiotics are the medications of choice, but tetracyclines and fluoroquinolones are also effective.

Mycoplasma does not have a cell wall, and is, therefore, intrinsically resistant to cell wall active agents such as beta lactam antibiotics. Sulfonamides, trimethoprin, and rifampin are also ineffective. Lincosamindes (clindamycin) appear to have low minimal inhibitory concentrations in vitro, but are not clinically effective. Oxazolidinones (drugs that target the 30S ribosome) do not show promise in vitro and should be avoided. Ketolides (such as telithromycin) show promise against M. pneumoniae in vitro, but clinical data in children are lacking, and the potential for liver toxicity has led to caution in using this antibiotic.

High dose glucocorticoids have been reported to be useful as adjunctive therapy in patients with mycoplasma encephalitis. Plasmapheresis and intravenous immunoglobulin therapy has also been used in such settings, but it is unclear whether these strategies offer substantial clinical benefit.

Macrolides and macrolide resistance

Studies in children with community-acquired pneumonia caused by mycoplasma have demonstrated that azithromycin and clarithromycin are as effective as erythromycin. Azithromycin and clarithromycin are generally preferred over erythromycin due to their greater tolerability, once or twice daily dosing, and shorter treatment duration for azithromycin, although their costs are greater.

Macrolide-resistant M. pneumoniae was first described in 2000, and is thought to result from selective pressure secondary to widespread increases in azithromycin use. Globally, China and Japan report macrolide resistance rates of 90% or higher. In 2011, a report from Israel noted a 30% resistance in organisms isolated from hospitalized patients. Some areas of Europe report resistance as high as 26%. In contrast, resistance rates in the Western hemisphere remain lower at 13% as of 2015.

Susceptibility testing is not routinely available and is only rarely performed, but the emergence of macrolide-resistant M. pneumoniae raises concerns about the usual empiric coverage choices in some parts of the world. Naturally occurring tetracycline- or fluoroquinolone-resistant strains have not yet been described.

Quinolones

Levofloxacin, moxifloxacin, gatifloxacin, and sparfloxacin have greater in vitro activity against mycoplasma than the older generation quinolones (ciprofloxacin, ofloxacin), although the minimal inhibitory concentrations for all quinolones are higher (and, thus, theoretically less effective) than for agents in the macrolide group.

What are the adverse effects associated with each treatment option?

Erythromycin is frequently associated with abdominal cramping, loss of appetite, and nausea. Vomiting or diarrhea is a common complaint during treatment. Rarely, allergic reactions occur. Cardiac dysrhythmias, including torsades de pointes have been described.

Azithromycin and clarithromycin therapy are less frequently associated with gastrointestinal complaints. Headaches occur in ~1% of patients. Rarely, these macrolides are associated with clinically significant hepatotoxicity or drug hypersensitivity syndromes.

Quinolone group antibiotics are associated with an increased risk for tendonitis and tendon rupture in all age groups. Risk increases further with concomitant use of glucocorticoids, and in patients with solid organ transplants.

What are the possible outcomes of Mycoplasma pneumoniae infection?

Almost all Mycoplasma pneumoniae infections carry an excellent prognosis; however, rare fatal cases from respiratory failure, acute hemolytic anemia, complications from erythema multiforme major, and encephalitis have been described.

What causes this disease and how frequent is it?

Surveillance in the United States indicates that mycoplasma is responsible for 15-20% of all community-acquired pneumonia (CAP). In Scandinavia, M. pneumoniae was detected in 30% of all pediatric CAP, and in over 50% among children older than 5 years. The incidence is greatest among school-aged children and declines after adolescence.

Serologic studies have shown that disease transmission occurs as cyclical epidemics every 3-5 years. The long incubation period, relatively low transmission rate, and persistence of the organism in the respiratory tract for variable periods following infection may explain why epidemics last for long period of time.

The incubation period may be as long as 3 weeks.

How do these pathogens/genes/exposures cause the disease?

Infection leads to ulceration and destruction of the ciliated epithelium of the respiratory tract with infiltration of macrophages, neutrophils, lymphocytes, and plasma cells. Diffuse alveolar damage may ensue in the most severe cases. Pleural effusions, bronchiectasis, abscess formation, and pulmonary fibrosis are rare but serious sequelae.

Other clinical manifestations that might help with diagnosis and management

Infection with M. pneumoniae has been suspected to play a role in several chronic inflammatory illnesses. The evidence for a role in asthma is more robust than for other illnesses, and infection has been linked to a skewed Th2-dominant inflammatory response during prolonged or chronic infection.

What complications might you expect from the disease or treatment of the disease?

Complications from pneumonia include the evolution of pleural effusions, or the development of respiratory failure, a rare but life-threatening problem. The formation of lung abscess has also been described.

In patients with dermatologic manifestations of infection, vigilance must be maintained regarding the development of erythema multiforme major. Such patients may need aggressive fluid and electrolyte support, and, in serious cases, airway assistance with mechanical ventilation is required, allowing the ulcerative process in the upper airway to heal.

How can Mycoplasma pneumoniae be prevented?

Antibiotic prophylaxis is not recommended after exposure. A vaccine is not available.

(The most current comprehensive and authoritative review available on the topic. The review ends with a summary table of all clinical trials done in children and adults to evaluate treatment options. The brief discussion about challenges in vaccine development is a highlight.)

(An excellent review for those interested in learning more about the pathogenesis and basic biology of mycoplasma. The section on laboratory testing is a strength of this review, as it provides balanced critiques of methods in serologic, culture, and PCR analysis.)

(Proposed mechanisms for the pathogenesis of neurologic manifestations in children after summarizing the experience with a large pediatric cohort are discussed.)

Ongoing controversies regarding etiology, diagnosis, treatment

Clinical evidence has offered a potential link between autoimmune disorders of the peripheral nervous system and the generation of pathologic antibodies against carbohydrate moieties on gangliosides, principally GM1. Between 5 and 15% of cases of Guillain-Barre Syndrome (GBS) have been associated with a preceding mycoplasma infection, but definitive proof of cause and effect remains elusive.

Recent infection with M. pneumoniae has been associated with the development of acute demyelinating encephalomyelitis (ADEM) and optic neuritis. Evidence linking such cases to the production of mycoplasma-induced autoantibodies is not as robust as for GBS.

Autoimmune phenomena seen following mycoplasma infection are thought to occur as a result of molecular mimecry. Mycoplasma adhesin proteins and several human tissues share amino acid sequence homology. Specifically, autoimmune antibodies can develop against the I antigen on erythrocytes, the CD4 moeity of the T cell receptor, and class II major histocompatibility complex antigens found on lymphocytes.

M. pneumoniae has only very rarely been cultured from cerebrospinal fluid of patients with meningoencephalitis, but when the more sensitive polymerase chain reaction testing is performed, organism-specific DNA is found more commonly. This failure to identify organisms in culture supports the contention that most central nervous system manifestations of mycoplasma infection are secondary to autoimmune phenomena rather than active infection of the CNS.